Regioselective cci-779 synthesis

FIELD: chemistry.

SUBSTANCE: regioselective synthesis of complex rapamycin 42-ether (CCI-779) involves: (a) acylation of 31-silyl rapamycin ether by compound of formula HOOC.CR7R8R9 or its combined anhydride, where: R7 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or -CO2R10; R10 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, triphenylmethyl, benzyl, alcoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl; R8 and R9 together form X; X is 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl can be optionally substituted; R12 and R13 each is independently hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, trifluormethyl or -F; and f=0-6; to obtain 42-ether boronate of 31-silyl rapamycin ether; (b) selective hydrolysis of 42-ether boronate of 31-silyl rapamycin ether in moderately acid environment to obtain rapamycin 42-ether boronate; and (c) diol treatment of rapamycin 42-etherboronate to obtain complex rapamycine 42-ether. Invention also claims new intermediate products applicable in this method.

EFFECT: application as antitumour medication.

48 cl, 3 ex

 

The level of invention

The present invention offers a regioselective synthesis of CCI-779, applicable as antitumor agents.

Complex 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an ester, which showed a significant inhibitory effect on tumor growth as in vitro models, and models in vivo.

CCI-779 may increase the period of tumor development or time of tumor recurrence, which is more typical cytostatic rather than cytotoxic agents. Believe that the mechanism of action of CCI-779 is similar to the mechanism of action of sirolimus. CCI-779 binds and forms a complex with the cytoplasmic protein FKBP, which inhibits the enzyme mTOR (target of rapamycin in mammals, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of the activity of mTOR kinase inhibits many cellular processes of signal transduction, including cell proliferation stimulated by cytokines, the translation of mRNA of some key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to the development of the cell cycle from G1 to S. the Mechanism of action of CCI-779, which leads to blocking the G1-S phase, is a new anti-cancer drugs.

It is shown that CCI-779 in vitro inhibits p the article number of histologically different tumor cells. The most sensitive to CCI-779 were cancer of the Central nervous system (CNS)leukemia (T-cell), breast cancer, and prostate cancer cell lines melanoma. This compound inhibited cells in the G1 phase of the cell cycle.

In experiments in vivo on naked mice shows that CCI-779 has activity against xenografts of human tumors of different histological types. Gliomas were particularly sensitive to CCI-779 and the connection was active models orthotopic gliomas on naked mice. Stimulation of cell lines of human glioblastoma caused by platelet growth factor, was significantly suppressed in vitro under the effect of CCI-779. The growth of some human pancreatic tumors in mice, as well as one of the two lines of breast cancer, was investigated in vivo, also inhibited under the effect of CCI-779.

Obtaining and applying complex hydroxyamino rapamycin, including CCI-779, disclosed in U.S. patent 5362718. Regiospecificity synthesis of CCI-779 described in U.S. patent 6277983.

CCI-779 can be synthesized deregistrations by acylation of rapamycin, as described in U.S. patent 5362718. This synthesis, however, is complicated by the formation of mixtures of the target 42-ester with 31-esterified by rapamycin, as well as with 31,42-diesterification by rapamycin and unreacted rapamycin.

CCI-779 can also be polustatsionarnom 31-salelologa ester of rapamycin by Cetelem bis(hydroxymethyl)propionic acid with posleduyushim removing 31-silylamines and Catalinas protective group bis(hydroxymethyl)propionic acid, as described in U.S. patent 6277983. However, crude complex 42-monoether obtained with this regioselective synthesis requires further purification column chromatography to remove residual quantities diapiric by-products and unreacted source of rapamycin.

The invention

The present invention offers a regioselective synthesis of 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779), based on chemistry Bronevoy acid. This izobreteniya eliminates complicated and, as a rule, time-consuming cleaning of complex 42-monoether rapamycin obtained previously used methods.

Other aspects and advantages of this invention will be easily understood from the following detailed description of the invention.

Detailed description of the invention

The present invention offers a regioselective synthesis of complex 42-ester of rapamycin by acylation 31-salelologa ester of rapamycin compound of the formula

.CR7R8R9

or a mixed anhydride, where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 and what Ohm carbon, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13each independently represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F;

and

f = 0-6;

with the formation of the 42-airborne 31-salelologa ester of rapamycin.

Next 42 boronat 31-ilililooo ester of rapamycin hydrolyzing in moderately acidic conditions with the formation of the 42-airbreath rapamycin. 42-Airborne rapamycin treated with appropriate diola. The method allows to obtain regiospecificity complex 42-ester of rapamycin.

Production, isolation and purification of complex 42-ester of rapamycin from salelologa ester of rapamycin in accordance with the method of this invention causes the reaction of perebrasyvaya in which phenylboronate the remainder of the connection turns into a diol. The deposition of complex 42-ester of rapamycin from a mixture of ether:heptane accompanies this pereoborudovanie. Synthetic path of the present invention has several distinct advantages over sravnenie the synthetic methodology published previously to obtain the esters and ethers of rapamycin; mainly in the clearing, the reduction in the cost of products, enhanced security, increased productivity and reduced production time. This method of the invention represents a new approach to the production of complex 42-ester of rapamycin (e.g., CCI-779). Time-consuming chromatographic stage, previously used in all large periodic ways of getting presents CCI-779, was excluded. A large amount of solvent required for chromatography, as described in U.S. patent 6277983 was unnecessary, resulting in decreased cost of products. Production time in the reactor and resources decreased by 50%. The size of the reactor required for large-scale synthesis of CCI-779, decreased, increased overall performance. A new methodology for perebrasyvaya described in this invention, reduces the overall process time. Purification method, included in the method of this invention eliminates the final treatment with diethyl ether in the previously described synthesis methods.

According to the invention 31-silloway ester of rapamycin acelerou using the connection formulas .CR7R8R9or its anhydride, defined above, to form a 31-silylated-42-afirmaron the TA. In one of embodiments 31-silloway ester of rapamycin acelerou, using 5-methyl-2-boronate[1,3-dioxane]-5-carboxylic acid (compound represented by [A] scheme 1 below) or 2,4,6-trichlorobenzoyl mixed anhydride of 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

One particularly successful method of getting 31-cyrilovich ethers of rapamycin are presented in U.S. patent 6277983. The present invention is not limited to this method of obtaining a 31-cyrilovich esters. However, in this paper, it is preferable that the 31-silloway ester of rapamycin was a 31-O-trimethylsilyloxy ester of rapamycin.

In one of embodiments 31-silloway ester of rapamycin differs in that it corresponds to the formula:

where R is selected from:

-O-C=.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X is particularly the 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13each independently represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F;

and

f = 0-6;

and where R', R" and R"' are the same or different and selected from alkyl with 1-6 carbon atoms, phenyl and benzyl.

The present invention features a compound [A] as a new connection, applicable for manufacture of CCI-779 and its analogues. Getting connection [A] involves mixing phenylboronic acid with 2,2-bis(hydroxymethyl)propionic acid at room temperature to obtain phenylboronate. Typically, the outputs are >90%. The reaction can be carried out in methylene chloride, but the preferred solvent is a tetrahydrofuran (THF).

Preferably, phenylboronic is a 2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, in which phenyl is optionally substituted. In another embodiment, phenylboronic is a 2-phenyl-1,3,2-dioxaborinane-4-yl, where the phenyl is optionally substituted. One particularly desirable substitution in the phenyl group is an alkyl, most desirable1With2With3With4With5or6alkyl. Other aryl- (including phenyl-) boranova KIS is the notes can be used in this reaction. They include mono, di and tri-substituted arylboronic acids in which the substituents are the same or different. The substituents in the aryl group include halogen, alkyl, alkoxy, aryloxy (for example, phenoxy), aralkyl, nitro, cyano, condensed phenyl which contains natalirodionova acid. The term "alkyl", when used in the case of a group or part of a group, such as alkoxy or aralkyl, includes alkyl fragments containing from 1 to 12 carbon atoms, e.g., 1-6 carbon atoms. The term "aryl" as a group or part of a group, for example, aralkyl or aryloxy, means an aromatic group containing substituents with 6-10 carbon atoms, such as phenyl or naphthyl. Preferred arylboronic acid is phenylboronic acid.

Finally, it is preferable that rapamycin bis-similarobama in positions 31 and 42 trimethylsilylpropyne with subsequent disilylgermane in position 42 with diluted sulfuric acid. The isolated product similarbut in position 42 anhydride, obtained from 2-phenylboronic acid. Dimethylaminopyridine was added as a catalyst to bring the reaction to completion. For the reaction required ˜3 equivalent of the mixed anhydride to spend the entire 31-trimethylsilylcyanation. After treatment of the reaction mixture polucen the th solution kept at a temperature of from 0 to 10° With, as he will not be required for the next stage. When standing in acetone, the product will undergo dissociation to the compound [B]. This fact is not a problem, because the next stage is the hydrolysis of the silyl functional group. Almost complete metamorphosis (< 3%) [B] was achieved through 83 days in acetone at a temperature of from 0 to 10°C.

The formation of the mixed anhydride can be controlled by REACTIR system (ASI Applied Systems). The REACTIR system (ASI Applied Systems) is a specially designed device for on-site analysis of various chemical reactions in real time. Provided that the mixed anhydride formed from carboxylic acids and carboxylic acid, the reaction is well suited for monitoring using infrared spectroscopy (IR). IR is an informative method for determining the presence of carbonyl functional groups, and in the case of REACTIR, to monitor the appearance or disappearance of carbonyl functional groups. In normal REACTIR (ASI Applied Systems) process connection [A] was mixed with diisopropylethylamine in methylene chloride and cooled to 0-5°in an ice bath. Registered IR spectrum, which serves as the initial scan. Then was added 2,4,6-trichlorobenzoyl. Filmed second IR spectrum, which characterizes the mixture at T=0 min ie the start of the reaction). The experiment was built with the removal of the IR spectra every 5 min for 5 h while maintaining the temperature of the bath is from 0 to 5°C. Key characteristic bands were at 1818 cm-1, 1741 cm-1and 1031 cm-1. When the acid chloride acid was added to a mixture of compound [A] and diisopropylethylamine (T=0 min), the spectrum is essentially showed no peak signal. However, the frequency of the carbonyl anhydride and (C-O-C) has increased over time, indicating the formation of a mixed anhydride.

The reaction of the mixed anhydride can be carried out in ethyl acetate, tert-butyllithium ether, diethyl ether and tetrahydrofuran (THF), but the reactions take place more slowly. The preferred solvent is a methylene chloride due facilitate completion of the reaction. DMAP is the preferred catalyst is the basis for this reaction. Other bases that may be used are 4-pyrrolidinone, N-Mei and pyridine.

The mixed anhydride is an unstable compound and is obtained in situ at low temperatures. It is stable up to 48 h at a temperature of from -5 to 0°C. It may be obtained at temperatures from -50 to 20°but the preferred temperature range is from -6 to 5°C. the Mixed anhydride can withstand up to 8 h per the e by the reaction of condensation. The preferred aging time is 4 to 5 h before the addition of 31-trimethylsilyl (TMS) rapamycin - partner condensation.

The condensation reaction can be carried out at temperatures from -20° to 20°but the preferred temperature range is from -11° -5°C. At higher temperatures the reaction slows down and to complete the required additional loading of the mixed anhydride. At lower temperatures, the mixed anhydride is more stable, however, the reaction time increases. The reaction is usually completed within from 12 to 17 hours

Connection [B] received, were isolated and purified in stage 3 the sequence of reactions carried out in a single reactor. The main element of this reaction consisted in the selection of acetone as a solvent. Other solvents that can be used in the receipt, include diethyl ether, acetonitrile, ethyl acetate, THF, tert-butyl methyl ether and methylene chloride. In the present work, acetone is the preferred solvent.

Thus, the 31-trimethylsilyl CCI-779, boronat, [D], was dissolved in acetone to obtain a concentrate. However, in some embodiments, the implementation of the hydrolysis can be carried out using a single-phase system of aqueous acid/organic solvent.

Hydrolysis 31-(trimethylsilyl) the Noah group (for education [B]) is carried out in moderately acidic conditions. Thus, the selected organic solvent (e.g. acetone) is mixed with diluted inorganic acid, such as, for example, sulfuric, hydrochloric or phosphoric acid. Examples of appropriate concentrations of the diluted acid are in the range of from about 0.1 G. to about 3 N., about 0.2 N. to about 2 N. or approximately 0.5 N. Typically, this stage is performed at a temperature of about 25°C or lower, from about -5°With up to about 10°From or from about 0°up to about 5°C. Preferably, this stage was carried out at pH 5 to 6. Optional, add to the mixture a suitable buffer, for example, sodium acetate or in the presence of sodium bicarbonate and/or acetic acid, to establish and maintain pH in the desired range.

In the examples below, the hydrolysis reaction is used 0,5 N. sulfuric acid at a temperature of from 0 to 5°C. the Reaction is normally complete within 5-6 hours and compound [B] was isolated by simple filtration. However, the use of reagents based on fluoride removal 31-trimethylsilyloxy groups is undesirable, formed as decomposition products.

Complex 42-airborne rapamycin is a new intermediate product is applicable in the method of the present invention to produce complex 42-ester of rapamycin. In one embodiment, is sushestvennee intermediate product is a complex 42-ester of rapamycin and 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

In one of the embodiments in this invention offers a complex 42-airborne rapamycin connection formula I:

where R is selected from:

-O-C=.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13are each, independently, hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F;

and

f = 0-6.

At this stage of the method of the invention 42-airborne rapamycin obtained by the method of the invention, is typically present In and With the isomers of the compounds. [These two isomer illustrative compounds [B] below]. At this stage, the ratio of the isomers In:C is usually <10:1. is the second invention installed, that isomer is more crystallinum than isomer and less soluble in acetone than With isomer. In order to take advantage of these properties, the authors showed that in nitroacetate buffer at pH 5 to 6, the ratio of the isomers In:can be increased up to about 20:1. By improving this relationship can be increased extraction of compound [B]. Thus, it is desirable to raise the ratio of isomers:until at least 1:1, more preferably greater than 5:1, above 10:1, higher than 15:1, about 20:1 and, more preferably, to about 25:1. Sodium bicarbonate was added to neutralize the sulfuric acid and the establishment of the pH to 7-8. Acetic acid was added to form sodium acetate and reduce the pH to 5-6. After keeping the reaction mixture for 16 h, the ratio of isomers is ˜25:1. Can be used in other buffers such as potassium acetate and zinc acetate, but the preferred buffer is sodium acetate.

The mixture was filtered, washed and dried to obtain a crude product of [B]. Royal solutions contain the vast quantity isomer, bis-ester by-products and other unknown impurities related to the crystalline crude initial product rapamycin.

To facilitate obtaining pure products is as important at this time to control the content of rapamycin in the crude compound [B]. The content of rapamycin is usually ˜5% (% area) according to high performance liquid chromatography (HPLC). Recrystallization reduce the amount of rapamycin to <0.7 percent. Cleaning in suitable solvents, such as acetone, can reduce the levels of rapamycin. Compound [B], shown in the diagram, is a white solid powder, which is stable at room temperature.

The reaction can be carried out in a solvent such as an ethereal solvent, or preferably THF, upon dilution of the reaction mixture of tert-butylmethylamine ether or toluene and the application of the method of water extraction to remove excess diol and gilbreath by-products. Both diol and gilbreath are water-soluble. The preferred method eliminates water extraction. The preferred method includes a simple stage filtration. The method comprises dissolving compound [B] in THF, tert-butyllithium ether or acetonitrile, adding a diol and stirring at room temperature for 3 hours the Solvent is removed by distillation to obtain a reaction mixture in the form of a foam/oil. Added ether and the product was Coosada heptane. The method can be repeated to obtain CCI-779 c output from 80% to 90%, based on the compound [B].

Initial processing diola removes the bulk fenil ronojoy acid in the reaction mixture. The residual amount of phenylboronic acid still present, can be removed by additional processing diola. The target compound [C], obtained by this method shows that the content of phenylboronic acid is acceptable. In the process of perebrasyvaya can be used an excess of diol, but the preferred amount is from 1 to 5 equivalents. The resulting output in this pereoborudovanie was 86%. The total yield from rapamycin ranged from 47 to 50%.

Many of 1,2-, 1,3-, 1,4 - and 1,5-diols can be used for carrying out this perebrasyvaya. Alkyl substituted diols, such as 2-methyl-2,4-pentanediol are preferred. Were applied diethanolamine or politicaleconomy on a solid substrate (PS-DEAM). Pereoborudovanie can also be achieved in the case of using the reagent of the class of carboxylic acids, such as oxalic, malonic, tartaric, phthalic and salicylic acid. 2,2-Bis(hydroxymethyl)propionic acid is also effective, but may not be removed from the final product.

The method shown in the following diagram. This scheme is only illustrative and does not limit the invention.

Getting 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, [A]

To a suspension of 2,2-bis(guide oxymethyl)propionic acid (131 g, 0.98 mol) in tetrahydrofuran (500 ml) was added a solution of phenylboronic acid (122 g, 1.0 mol) in tetrahydrofuran (500 ml). The mixture was stirred for 3 h and was added toluene (1.0 l). Water was removed by azeotropic distillation with toluene. To the precipitated product was added heptane (500 ml)was heated at boiling under reflux and cooled. The mixture was filtered and washed with heptane (2 × 300 ml). The precipitate was dried in vacuum at 70-75°C to constant mass, receiving the output of 94%.1H NMR: δ (DMSO-d6) of 7.65 (d, 2H, Ar), 7,40 (m, 3H, Ar), 4,35 (d, 2H, CH2), to 3.92 (d, 2H, CH2), of 1.17 (s, 3H, CH3).

Obtaining complex 42-ester of rapamycin and 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid [B]

As described in U.S. patent 6277983 (2001), in a 3-liter flask were placed rapamycin (100 g, 0.104 g mol) was dissolved in ethyl acetate (1.50 l). The solution was cooled to 5-10°C. was Added imidazole (30 g, 0.44 mol, 4,23 EQ.) and dissolved. In an atmosphere of nitrogen was added trimethylsilane (44 g, 0,405 mol, 4.0 EQ.) within 30-40 min, keeping the temperature at 0-5°during the addition. The mixture was stirred for at least 0.5 hours the Reaction was controlled by TLC (eluent acetone:heptane 30:70). The reaction was completed, when the whole rapamycin was spent.

Took two or three drops of the reaction mixture and kept them as 31,42-bis(trimethylsilyl)rapamycin etal the frame of the standard. 0,5 N. Sulfuric acid (300 ml) was added 3-liter flask for 0.5 h, keeping the temperature between 0-5°C. the Mixture was intensively mixed and maintained for 5 hours the Reaction was monitored by thin-layer chromatography (TLC) (eluent acetone:heptane 30:70). The reaction was completed, when was essentially absent 31,42-bis(trimethylsilyl)rapamycin. The layers were separated and the lower aqueous layer was again extracted with ethyl acetate (500 ml). The combined organic layers were washed with saturated brine (500 ml) and a saturated solution of sodium bicarbonate (2 × 200 ml) until pH 8. The organic layer was washed with water (2 x500 ml) and saturated brine (500 ml) until pH 6 to 7. The solution was dried over magnesium sulfate (100 g) for 30 min, filtered in a 2-liter flask and concentrated to a volume of 135 ml) was Added ethyl acetate (500 ml) and mass was concentrated to a volume of 135 ml of the Aqueous phase is again treated with ethyl acetate (500 ml). Added methylene chloride (300 ml) and the solution was kept until it is needed for the next stage.

A 3-liter flask equipped with a mechanical stirrer, was loaded connection [A] (75 g, 0,341 mol) in methylene chloride (400 ml). Diisopropylethylamine (66,1 g, 0.51 mol) was added dropwise over 20 min and Strahovanie with methylene chloride (25 ml). 2,4,6-Trichlorobenzoyl (80 g, 0,328 mol) was added and dissolved in Meiling what oridam (25 ml). The mixture was stirred for 4 h at 0-5°and cooled to -10±5°C.

A solution of 31-trimethylsilylimidazole was added to a 3-liter flask containing the mixed anhydride, and shaken with methylene chloride (25 ml). Got the solution dimethylaminopyridine (48,5 g, 0,397 mol) in methylene chloride (150 ml)was added for 1.5 h, keeping the temperature <-8°C, and shaken with methylene chloride (25 ml). The mixture was stirred for 12 h at temperatures ranging from -11 to -5°C. the Reaction mixture is extinguished 1 N. sulfuric acid (600 ml), keeping the temperature < 10°C. the Mixture was stirred and kept for 30 minutes the pH Value of the upper water layer was ≤2. The layers were separated and the lower organic layers were washed with saturated brine (450 ml), saturated sodium bicarbonate (500 ml) to pH ≥8. The organic layer was washed with water (450 ml) until pH 6-7. The solution was concentrated, and acetone was added (250 ml) and concentrated. The procedure was repeated with another portion of acetone (250 ml) and the solution was concentrated.

The solution was diluted with acetone. Was added dropwise to 0.5 N. sulfuric acid (500 ml) for 30 min, maintaining the bath temperature at 0-5°C. the Mixture was stirred for at least 5 h, during which time the product precipitated from solution. Aqueous sodium bicarbonate (30 g in 375 ml of water) was added dropwise over 30 min, maintaining the temperature of the Ani from 0 to 5° C; the mixture was stirred for at least 30 minutes was Added acetic acid (25 ml)until the pH does not become equal to 5-6, maintaining the bath temperature <10°C. the Mixture was heated to room temperature and kept for 16 hours, the Solid product was filtered and washed with water (2 × 100 ml), then with a mixture of 1:1 acetone:water (2 x 100 ml). The residue was purified in acetone (375 ml)to give 65 g (total yield 58% relative to rapamycin) product [B]. LC/MS: using electrospray ionization in the registration mode, the positive ions led to a molecular ion [M+Na]=1138,5 of atomic mass units (Amu).

Obtaining complex 42-ester of rapamycin with 2,2-bis(hydroxymethyl)propionic acid, [C]

Connection [B] (200 g, 0,179 mol) was dissolved in tetrahydrofuran (600 ml), were added 2-methyl-2,4-pentanediol (42,3 g, 0,358 mol, 2.0 EQ.) and the mixture was stirred for a minimum of 3 hours the Reaction mixture was concentrated to a foam. Added diethyl ether (1.0 l) and the mixture was stirred for 2 hours was Added dropwise heptane (1.0 l) for 1 h and the mixture was stirred for 2 h the Mixture was filtered and the solid product was washed with heptane (500 ml). Solid was re-dissolved in acetone (400 ml), was re-treated with 2-methyl-2,4-pentanediol (21.1 g, 0,179 mol, 1 EQ.) in acetone (200 ml), was purified using the 0.2-micron cartridge filter and shook the with acetone (200 ml). The solution was concentrated to a foam which was added diethyl ether (1.0 l), pre-filtered through the 0.2 micron cartridge filter, and the mixture was stirred for 2 h was Observed precipitation by adding pre-filtered heptanol (1.0 l). Precipitated precipitated solids were filtered and washed with ether:heptane (2 × 500 ml). The solids were dried (55 to 60°C, 10 mm Hg, 24 h)to give 159 g (86%) of product [C]. LC/MS: using APCI in scan mode positive ions led to a molecular ion [M+NH4]=1047,0 u1H NMR of the product (CCI-779) was identical to the product described in example 11 of U.S. patent 5362718 (1994).

All patents, patent applications, articles and other documents related to this paper, incorporated herein by reference. The person skilled in the art it will be obvious that the particular embodiments of described herein may be amended, not beyond the scope of this invention.

1. The method of obtaining complex 42-ester of rapamycin, which includes

(a) acylation 31-salelologa ester of rapamycin compound of the formula

HOOC.CR7R8R9

or a mixed anhydride,

where R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil is 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13each, independently, represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F; and

f=0-6;

for education 42-airbreath 31-salelologa ester of rapamycin;

(b) selective hydrolysis 42-airbreath 31-salelologa ether in moderately acidic conditions to obtain a 42-airbreath rapamycin; and

(C) processing of 42-airbreath rapamycin diola to obtain complex 42-ester of rapamycin.

2. The method according to claim 1, wherein the received complex 42-ester of rapamycin is a CCI-779, and in which stage (a) comprises the acylation 31-salelologa ester of rapamycin 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, or a mixed anhydride of 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid for the floor is to be placed 42-airbreath 31-O-salelologa ester of rapamycin.

3. The method according to any one of claims 1 or 2, where the 31-similarity fragment corresponds to the formula

-OSiR'R"R"',

in which R', R" and R"' are the same or different and selected from alkyl with 1-6 carbon atoms, phenyl and benzyl.

4. The method according to any one of claims 1 or 2, where the 31-silloway ether is trimethylsilyloxy ether.

5. The method according to any one of claims 1 or 2, where the acylation stage (a) is performed with 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

6. The method according to any one of claims 1 or 2, where the acylation stage (a) is made using 2,4,6-trichlorobenzoyl mixed anhydride of 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

7. The method according to any one of claims 1 or 2, where the acylation stage (a) is performed at less than about 20°C.

8. The method according to claim 7, which is performed at a temperature of from about -50°With up to about 20°C.

9. The method according to any one of claims 1 or 2, in which stage (a) is performed in a solvent comprising methylene chloride.

10. The method according to any one of claims 1 or 2 where the acid in stage (b) is a dilute inorganic acid.

11. The method according to claim 10, where the acid is a sulfuric, hydrochloric or phosphoric acid.

12. The method according to claim 11, where applied in stage (b) acid is serouisly.

13. The method according to claim 10, where applied in stage (b) acid is the acid from about 0.1 G. to about 3 N.

14. The method according to item 13, where the acid in stage (b) is an acid from approximately 0.2 BC to about 2 N.

15. The method according to item 13, where the applied acid in stage (b) is a 0.5-called acid.

16. The method according to any one of claims 1 or 2, where stage (b) is performed in a single-phase system of water acid/organic solvent.

17. The method according to clause 16, where the organic solvent is acetone.

18. The method according to any one of claims 1 or 2, where stage (b) is performed at a temperature of from about 25°With or below.

19. The method according to p, where stage (b) is performed at a temperature of from about -5°With up to about 10°C.

20. The method according to p, where stage (b) is performed at a temperature of from about 0°up to about 5°C.

21. The method according to any one of claims 1 or 2, in which applied at the stage (C) diol is a 1,2-, 1,3-, 1,4 - or 1,5-diol.

22. The method according to item 21, in which the diol is 2-methyl-2,4-pentanediol.

23. The method according to any one of claims 1 or 2, in which the diol at the stage (C) is applied in an amount of from about 1 to about 5 mol equivalents.

24. The method according to any one of claims 1 or 2, wherein stage (C) is performed at a temperature of from about -5°C to about +25°C.

25. The method according to any one who has one of claims 1 or 2, in which stage (s) performed in the presence of tetrahydrofuran.

26. The method according to any one of claims 1 or 2, which is made in the presence of simple ether.

27. The method according to claim 1, in which the 42-airborne 31-O-trimethylsilyl ester of rapamycin corresponds to the formula

in which R represents-O-C=O.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8andR9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13each, independently, represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F; and

f=0-6;

R', R" and R"' are the same or different and selected from alkyl with 1-6 carbon atoms, f is the Nile and benzyl.

28. The method according to claim 1, where the 42-airborne rapamycin corresponds to the formula

in which R represents-O-C=O.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13each, independently, represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F; and

f=0-6.

29. The method of obtaining the compounds of formula

which includes the processing of 42-airbreath 31-salelologa ester of rapamycin appropriate diola.

30. The method according to clause 29, which is applied diol is a 1,2-, 1,3-, 1,4 - or 1,5-diol.

31. The method according to Liu the WMD one PP or 30, in which the diol is 2-methyl-2,4-pentanediol.

32. The method according to any one PP or 30, in which the diol used in an amount of from about 1 to about 5 mol equivalents.

33. The method according to any one PP or 30, which is performed at a temperature of from about -5°C to about +25°C.

34. The method according to any one PP or 30, which is made in the presence of tetrahydrofuran.

35. The method according to any one PP or 30, which is made in the presence of simple ether.

36. The way to obtain 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, which comprises the interaction of 2,2-bis(hydroxymethyl)propionic acid with phenylboronic acid.

37. The method according to p, which is made in the presence of tetrahydrofuran.

38. A method of improving the purity of the compounds of formula

in the solution containing the isomers b and C in the ratio of < about 10:1,

comprising a stage of bringing the pH of the solution to a pH of approximately from 5 to 6.

39. The method according to § 38, which is made in the presence of acetone.

40. The method according to § 38 or 39, which is made in the presence of nitroacetate buffer.

41. The method according to § 38 or 39, which is made in the presence of sodium bicarbonate or acetic acid.

42. The compound of formula (I)

in which R is selected from

-O-C=O.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13are each, independently, hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms,

trifluoromethyl or-F; and

f=0-6.

43. The compound of the formula

in which R is chosen from:

-O-C=O.CR7R8R9where

R7represents hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or-CO2R10;

R10represents the waters of the genus, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl;

R8and R9taken together, form X;

X represents 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl may be optionally substituted;

R12and R13are each, independently, hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, quinil with 2-7 carbon atoms, trifluoromethyl or-F; and

f=0-6;

and where R', R" and R"' are the same or different and selected from alkyl with 1-6 carbon atoms, phenyl and benzyl.

44. Connection, which is a complex 42-ester of rapamycin and 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

45. Connection, which is a complex 42-ester 31-O-trimethylsilyl ester of rapamycin and 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.

46. The compound of the formula

HO-C=O.CR7R8R9

in which R7, R8and R9take the values defined in claim 1.

47. Connection p.46, which represents 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, where the phenyl is optionally substituted.

48. Connection p.46,which represents 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.



 

Same patents:

FIELD: chemistry.

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EFFECT: creation of efficient method of obtaining alkali metal cyanoborates.

18 cl, 26 ex, 1 tbl

FIELD: medicine, radiation therapy.

SUBSTANCE: the present innovation refers to radiosensitizers that contain as an active component halogenated derivatives of borated porphyrines that contain a great number of carboranic cells which are selectively accumulated in neoplasms' tissues in the irradiated volume and could be applied in such type of cancer therapy that include but are not restricted with boron-neutron-capturing therapy and photodynamic therapy. The present innovation , also, deals with applying these radiosensitizers for visualization of the tumor and treating the cancer.

EFFECT: higher efficiency.

35 cl, 2 dwg, 8 ex, 7 tbl

FIELD: physical analytical methods.

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EFFECT: increased efficiency of bioanalyses.

5 cl, 5 dwg, 5 tbl, 25 ex

FIELD: polymer materials.

SUBSTANCE: invention provides luminescent material showing semiconductor properties and being product of complex polymerization in glow discharge, which is formed as a supported polymer layer located either between electrodes or on any of electrodes. Starting pyrromethene complex is difluoroborate complex of 1,3,5,7,8-pentamethyl-2,6-diethylpyrromethene (Pyrromethene 567). Method of preparing luminescent semiconductor polymer material comprises glow-discharge polymerization for 2 to 120 min of Pyrromethene 567 vapors at temperature preferably 250-350°C, pressure 10-1 to 10-2 Pa, and discharge power 0.5-3 W. Resulting luminescent polymer is characterized by thickness preferably 0.001-10 μm, conductivity 1·10-10 to 5·10-10 Ohm-1cm-1 (20°C), luminescence emission maximum in the region of 540-585 nm at band halfwidth 55-75 nm. Polymer is obtained with quantum yield 0.6-0.8 and is designed for creation of film light-emitting devices.

EFFECT: improved performance characteristics of material.

13 cl, 3 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: disclosed method for production of [R-(R*,R*)}]-2-(4-fluoriphenyl)-β,δ-dihydroxy-5-(1-methyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-heptanoic acid semi-calcium salt (atorvastatin) of formula XII includes reaction of preprepared compound of formula Xa with compound of formula IV in solvent mixture selected from group containing xylene, cyclohexane, methyl-tert-butyl ether, diisopropyl ether, acetonitrile, in presence of catalyst selected from group containing pivalic acid, trifluotomethylsulfonic acid, methanesulfonic acid or p-toluenesulfonic acid to form intermediate of formula XIa , followed by hydrolysis of formula XIa and calcium salt production to form target product of formula XII. Claimed compound represents enzyme hydroxymethylglutaryl-CoA reductase inhibitor, and thereby is useful as hypolipidemic and hypocholesteronemic agents.

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7 cl, 2 dwg, 9 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for preparing organoboron compounds, in particular, pinacol borane (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) representing a monofunctional hydride-borating agent for alkenes and alkynes and for Suzuki's cross-coupling reaction also. Method is carried out by interaction of pinacol (2,2,3,3-tetramethylethylene glycol, 2,3-dimethyl, 2,3-butanediol) with borane reagent in the presence of a solvent and the following isolation of the end product. Gaseous diborane is used as a borane reagent and the process is carried out in diethyl ether medium at range of temperatures 5-36°C, and the process is carried out in the mole ratio of reagents pinacol : diborane = 1:(0.45-0.55), respectively; or the method is carried out by interaction of pinacol with borane reagent and the following isolation of the end product wherein gaseous diborane is used as a borane reagent, and the process is carried out in pinacol melt at temperature ranges 40-80°C. The process is carried in the mole ratio of reagents pinacol : diborane = 1:(0.45-0.55), respectively. Method provides preparing pinacol borane with high yield 90-95% and high purity 99.5-99.8%. Method shows technological simplicity and economy profit in realization in the industrial scale.

EFFECT: improved preparing method.

3 cl, 4 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for preparing organoboron compounds, in particular, to the improved method for preparing 9-borabicyclo[3.3.1]nonane. Method for preparing 9-borabicyclo[3.3.1]nonane is carried out by interaction of diborane with 1,5-cyclooctadiene in 1,4-dioxane medium at simultaneous feeding diborane and 1,5-cyclooctadiene at the rate necessary for maintaining the molar ratio 1,5-cyclooctadiene : diborane = (1.9-2.04):1.0, respectively, during all through reaction. The process is carried out in the volume ratio 1,4-dioxane : 1,5-cyclooctadiene = (2.2-4.0):1.0 and at temperature 11-25°C. In preparing 9-borabicyclo[3.3.1]nonane the reaction mass is kept at temperature 65-102°C. The invention provides simplifying technology in preparing 9-borabicyclo[3.3.1]nonane due to exclusion the preliminary preparing borane complex and additional recrystallization of 9-borabicyclo[3.3.1]nonane, enhancing yield of the end product up to 91.0-93.5% of the high quality (the content of basic substance is 99.1-99.9%, melting point is 152-156°C), and possibility for creating the wasteless manufacturing. Method for preparing 9-borabicyclo[3.3.1]nonane shows technological simplicity in its realization and economy profit in its realization in industrial scale.

EFFECT: improved preparing method.

4 cl, 4 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to organoboron compounds technology, in particular to aminoboranes and, more specifically, to trimethylaminoborane, which can be used as reducing and hydroboronizing agents as well as in color photography, in magnetic film manufacture, and as fuel additive to decrease amount of deposits in combustion chamber. Method comprises reaction of trimethylamine with gaseous diborane in organic solvent at reduced temperature. Solvent is selected from aliphatic, cycloaliphatic, and aromatic hydrocarbons with melting temperature not higher than -20°C. Reaction is conducted at temperature from -30°C to 0°C, preferably from -15 to -5°C, at trimethylamine-to-solvent volume ratio 1:(1/5-3.5).Proposed method simplifies preparation procedure owing to eliminated laborious solvent removing vacuum distillation stage and stage wherein of aqueous alkali metal hydroxide is introduced to stabilize aminoborane. Yield of desired product, characterized by high purity, achieves 95-98.6%, which is essentially higher than, for example yield (86%) of morpholinoborane regarded as prototype compound in a known process.

EFFECT: enhanced economical efficiency of process.

3 cl, 4 ex

FIELD: chemistry of complex compounds.

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EFFECT: improved method for preparing.

20 cl, 14 ex

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EFFECT: valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to some new macroheterocyclic compounds that can act as selective inhibitors of kinase or double kinase. Invention describes compounds of the following formulae: formula (Ia1), formula (Ib1), formula (If1), formula (Ii1), and formula (Ij1) wherein values R2, R4 and R5 are chosen by the dependent manner as given in the invention claim. Invention provides preparing new compounds possessing valuable biological properties.

EFFECT: valuable biological properties of compounds.

5 cl, 3 tbl, 22 ex

Derivative to-a // 2205184
The invention relates to new derivatives of K-a (a derivative of indolocarbazole), which are represented by the General formula 1, as well as to a method for improving the functioning and/or increase the survival of cholinergic neurons and the way to improve cell survival at risk of death because of the compounds of formula 1 inhibit production of interleukin-2 and have immunosuppressive activity

The invention relates to novel analogues of camptothecin, in particular to the compounds corresponding to the following formulas (I) and (II), as well as their racemic or enantiomeric forms or combinations of these forms, where the substituents have the values

The invention relates to a new class of chemical compounds, namely to derive a new heterocyclic system - tetrabenazine[3,4-b:3',4'-f: 3", 4"-j: 3"', 4"'-n-[1,4,5,8,9,12,13,16]-actuatable[14.2.2]eicosa-4,8,12-triens General formula (I), where R1- R4= H, lower alkyl or lower alkyl containing functional groups, such as or SIG5, SR5, NR5R6, СОNR5R6or СООR7where R5, R6, R7= H, lower alkyl, or R2+ R3and/or R1+ R4together with the neighboring carbon atoms pieperazinove cycle form an alicyclic, benzene or heterocyclic annelirovannymi cycle

The invention relates to water-soluble derivative of camptothecin described by formula (I)

< / BR>
where n = 1 or 2; 1) R1and R2taken separately, represent hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; 2) R1represents hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or lower alkoxy lower alkyl; R2is-COR3where R3represents hydrogen, lower alkyl, pergola-lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl, lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl; 3) R1and R2taken together with the connecting nitrogen atom form a saturated 3-7-atom heterocyclic group of formula 1A

< / BR>
where Y represents O, S, CH2, NR4where R4represents hydrogen, lower alkyl, pergola-lower alkyl, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyloxy lower alkyl, or COR5where R5represents hydrogen, lower alkyl, pergola-lower alkyl, lower alkoxy, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyl, pergola-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl; and their pharmaceutically acceptable salts, their use for the treatment of tumors and methods of preparation

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to some new macroheterocyclic compounds that can act as selective inhibitors of kinase or double kinase. Invention describes compounds of the following formulae: formula (Ia1), formula (Ib1), formula (If1), formula (Ii1), and formula (Ij1) wherein values R2, R4 and R5 are chosen by the dependent manner as given in the invention claim. Invention provides preparing new compounds possessing valuable biological properties.

EFFECT: valuable biological properties of compounds.

5 cl, 3 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: regioselective synthesis of complex rapamycin 42-ether (CCI-779) involves: (a) acylation of 31-silyl rapamycin ether by compound of formula HOOC.CR7R8R9 or its combined anhydride, where: R7 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or -CO2R10; R10 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, triphenylmethyl, benzyl, alcoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl; R8 and R9 together form X; X is 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl can be optionally substituted; R12 and R13 each is independently hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, trifluormethyl or -F; and f=0-6; to obtain 42-ether boronate of 31-silyl rapamycin ether; (b) selective hydrolysis of 42-ether boronate of 31-silyl rapamycin ether in moderately acid environment to obtain rapamycin 42-ether boronate; and (c) diol treatment of rapamycin 42-etherboronate to obtain complex rapamycine 42-ether. Invention also claims new intermediate products applicable in this method.

EFFECT: application as antitumour medication.

48 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of the formula , where R1 and R2 are different independent groups and are selected from the group consisting of OR3 and N (R3') (R3"); or R1 and R2 are different groups connected through a single bond and selected from the group consisting of O and NR3; R3, R3', and R3" are independently selected from the group consisting of H, phenyl, substituted phenyl, where substituents are independently selected from the group consisting of C1-C6 alkyl, halogen; R4 and R4': (a) independently selected from the group consisting of H, OH, a group of the formula ; R5, R6, and R7 are independently selected from the group consisting of OCH3; R8 and R9 are joined by (i) a single bond and represent CH2 or (ii) double bond and are CH; R15 are selected from the group consisting of C=O; n is equal to 2. The invention also refers to method for obtaining these compounds.

EFFECT: obtaining new compounds which can be used in medicine as neurodefensive and neurogenerative, antiproliferative and anti-inflammatory drugs.

43 cl, 7 tbl, 13 ex

Organic compounds // 2394038

FIELD: medicine.

SUBSTANCE: new crystal form II N-benzoilstaurosporin is described, as well as pharmaceutical composition containing it, inhibiting protein kinase C; ways of obtaining crystalline form of compounds, and the use of crystal form of II N-benzoilstaurosporin for treatment neoplastic diseases. Crystalline form of II N-benzoilstaurosporin is a stable form of N-benzoilstaurosporin with low hygroscopicity.

EFFECT: suitability in pharmaceutical compositions.

21 cl, 2 tbl, 4 dwg, 16 ex

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